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Molecular Aspects of Medicine Dec 2014Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death,... (Review)
Review
Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed high-mobility group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhibitors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localization, structure, post-translational modification, and identification of additional partners will undoubtedly uncover additional secrets regarding HMGB1's multiple functions.
Topics: Disease; HMGB1 Protein; Health; Humans
PubMed: 25010388
DOI: 10.1016/j.mam.2014.05.001 -
International Journal of Molecular... Jan 2020Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can... (Review)
Review
Chromatin plays a key role in regulating gene expression programs necessary for the orderly progress of development and for preventing changes in cell identity that can lead to disease. The high mobility group N (HMGN) is a family of nucleosome binding proteins that preferentially binds to chromatin regulatory sites including enhancers and promoters. HMGN proteins are ubiquitously expressed in all vertebrate cells potentially affecting chromatin function and epigenetic regulation in multiple cell types. Here, we review studies aimed at elucidating the biological function of HMGN proteins, focusing on their possible role in vertebrate development and the etiology of disease. The data indicate that changes in HMGN levels lead to cell type-specific phenotypes, suggesting that HMGN optimize epigenetic processes necessary for maintaining cell identity and for proper execution of specific cellular functions. This manuscript contains tables that can be used as a comprehensive resource for all the English written manuscripts describing research aimed at elucidating the biological function of the HMGN protein family.
Topics: Animals; Chromatin; Disease; Epigenesis, Genetic; Gene Expression Regulation, Developmental; HMGN Proteins; High Mobility Group Proteins; Humans; Mice; Promoter Regions, Genetic
PubMed: 31936777
DOI: 10.3390/ijms21020449 -
Epigenetics & Chromatin Jun 2022Nucleosomal binding proteins, HMGN, is a family of chromatin architectural proteins that are expressed in all vertebrate nuclei. Although previous studies have...
BACKGROUND
Nucleosomal binding proteins, HMGN, is a family of chromatin architectural proteins that are expressed in all vertebrate nuclei. Although previous studies have discovered that HMGN proteins have important roles in gene regulation and chromatin accessibility, whether and how HMGN proteins affect higher order chromatin status remains unknown.
RESULTS
We examined the roles that HMGN1 and HMGN2 proteins play in higher order chromatin structures in three different cell types. We interrogated data generated in situ, using several techniques, including Hi-C, Promoter Capture Hi-C, ChIP-seq, and ChIP-MS. Our results show that HMGN proteins occupy the A compartment in the 3D nucleus space. In particular, HMGN proteins occupy genomic regions involved in cell-type-specific long-range promoter-enhancer interactions. Interestingly, depletion of HMGN proteins in the three different cell types does not cause structural changes in higher order chromatin, i.e., in topologically associated domains (TADs) and in A/B compartment scores. Using ChIP-seq combined with mass spectrometry, we discovered protein partners that are directly associated with or neighbors of HMGNs on nucleosomes.
CONCLUSIONS
We determined how HMGN chromatin architectural proteins are positioned within a 3D nucleus space, including the identification of their binding partners in mononucleosomes. Our research indicates that HMGN proteins localize to active chromatin compartments but do not have major effects on 3D higher order chromatin structure and that their binding to chromatin is not dependent on specific protein partners.
Topics: Chromatin; Epigenesis, Genetic; HMGN Proteins; Nucleosomes; Protein Binding
PubMed: 35761366
DOI: 10.1186/s13072-022-00457-4 -
Nature Communications Nov 2022White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We...
White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.
Topics: Male; Animals; Mice; Nucleosomes; Adipose Tissue, Brown; HMGN Proteins; Epigenesis, Genetic; Fibroblasts; Adipose Tissue, White; Adipocytes, Brown; Energy Metabolism
PubMed: 36435799
DOI: 10.1038/s41467-022-34964-5 -
Nucleic Acids Research Apr 2017An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not...
An interplay between the nucleosome binding proteins H1 and HMGN is known to affect chromatin dynamics, but the biological significance of this interplay is still not clear. We find that during embryonic stem cell differentiation loss of HMGNs leads to down regulation of genes involved in neural differentiation, and that the transcription factor OLIG2 is a central node in the affected pathway. Loss of HMGNs affects the expression of OLIG2 as well as that of OLIG1, two transcription factors that are crucial for oligodendrocyte lineage specification and nerve myelination. Loss of HMGNs increases the chromatin binding of histone H1, thereby recruiting the histone methyltransferase EZH2 and elevating H3K27me3 levels, thus conferring a repressive epigenetic signature at Olig1&2 sites. Embryonic stem cells lacking HMGNs show reduced ability to differentiate towards the oligodendrocyte lineage, and mice lacking HMGNs show reduced oligodendrocyte count and decreased spinal cord myelination, and display related neurological phenotypes. Thus, the presence of HMGN proteins is required for proper expression of neural differentiation genes during embryonic stem cell differentiation. Specifically, we demonstrate that the dynamic interplay between HMGNs and H1 in chromatin epigenetically regulates the expression of OLIG1&2, thereby affecting oligodendrocyte development and myelination, and mouse behavior.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Differentiation; Cell Line; Embryonic Stem Cells; Enhancer of Zeste Homolog 2 Protein; Epigenesis, Genetic; Female; HMGN Proteins; HMGN1 Protein; HMGN2 Protein; Histones; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Oligodendroglia
PubMed: 27923998
DOI: 10.1093/nar/gkw1222 -
Nucleic Acids Research Sep 2016The activation of naïve B lymphocyte involves rapid and major changes in chromatin organization and gene expression; however, the complete repertoire of nuclear factors...
The activation of naïve B lymphocyte involves rapid and major changes in chromatin organization and gene expression; however, the complete repertoire of nuclear factors affecting these genomic changes is not known. We report that HMGN proteins, which bind to nucleosomes and affect chromatin structure and function, co-localize with, and maintain the intensity of DNase I hypersensitive sites genome wide, in resting but not in activated B cells. Transcription analyses of resting and activated B cells from wild-type and Hmgn(-/-) mice, show that loss of HMGNs dampens the magnitude of the transcriptional response and alters the pattern of gene expression during the course of B-cell activation; defense response genes are most affected at the onset of activation. Our study provides insights into the biological function of the ubiquitous HMGN chromatin binding proteins and into epigenetic processes that affect the fidelity of the transcriptional response during the activation of B cell lymphocytes.
Topics: Animals; B-Lymphocytes; Chromatin; Deoxyribonuclease I; Epigenesis, Genetic; Gene Expression Regulation; HMGN Proteins; HMGN1 Protein; HMGN2 Protein; Lymphocyte Activation; Male; Mice; Nucleosomes; Promoter Regions, Genetic; Protein Binding; Regulatory Sequences, Nucleic Acid; Spleen
PubMed: 27112571
DOI: 10.1093/nar/gkw323 -
Genes Dec 2021DNA methylation and histone posttranslational modifications are epigenetics processes that contribute to neurophenotype of Down Syndrome (DS). Previous reports present...
DNA methylation and histone posttranslational modifications are epigenetics processes that contribute to neurophenotype of Down Syndrome (DS). Previous reports present strong evidence that nonhistone high-mobility-group N proteins (HMGN) are epigenetic regulators. They play important functions in various process to maintain homeostasis in the brain. We aimed to analyze the differential expression of five human HMGN genes in some brain structures and age ranks from DS postmortem brain samples. We performed a computational analysis of the expression of human HMGN from the data of a DNA microarray experiment (GEO database ID GSE59630). Using the transformed log2 data, we analyzed the differential expression of five HMGN genes in several brain areas associated with cognition in patients with DS. Moreover, using information from different genome databases, we explored the co-expression and protein interactions of HMNGs with the histones of nucleosome core particle and linker H1 histone. We registered that HMGN1 and HMGN5 were significantly overexpressed in the hippocampus and areas of prefrontal cortex including DFC, OFC, and VFC of DS patients. Age-rank comparisons between euploid control and DS individuals showed that HMGN2 and HMGN4 were overexpressed in the DS brain at 16 to 22 gestation weeks. From the BioGRID database, we registered high interaction scores of HMGN2 and HMGN4 with Hist1H1A and Hist1H3A. Overall, our results give strong evidence to propose that DS would be an epigenetics-based aneuploidy. Remodeling brain chromatin by HMGN1 and HMGN5 would be an essential pathway in the modification of brain homeostasis in DS.
Topics: Brain; Brain Mapping; Cognition; Databases, Genetic; Down Syndrome; Epigenesis, Genetic; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; HMGN Proteins; HMGN1 Protein; HMGN2 Protein; Hippocampus; Humans; Nucleosomes; Prefrontal Cortex; Trans-Activators; Transcription Factors; Transcriptome
PubMed: 34946949
DOI: 10.3390/genes12122000 -
Communications Biology Feb 2022Nucleosomes containing acetylated H3K27 are a major epigenetic mark of active chromatin and identify cell-type specific chromatin regulatory regions which serve as...
Nucleosomes containing acetylated H3K27 are a major epigenetic mark of active chromatin and identify cell-type specific chromatin regulatory regions which serve as binding sites for transcription factors. Here we show that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 bind preferentially to H3K27ac nucleosomes at cell-type specific chromatin regulatory regions. HMGNs bind directly to the acetylated nucleosome; the H3K27ac residue and linker DNA facilitate the preferential binding of HMGNs to the modified nucleosomes. Loss of HMGNs increases the levels of H3K27me3 and the histone H1 occupancy at enhancers and promoters and alters the interaction of transcription factors with chromatin. These experiments indicate that the H3K27ac epigenetic mark enhances the interaction of architectural protein with chromatin regulatory sites and identify determinants that facilitate the localization of HMGN proteins at regulatory sites to modulate cell-type specific gene expression.
Topics: Chromatin; HMGN Proteins; Nucleosomes; Protein Binding; Transcription Factors
PubMed: 35197580
DOI: 10.1038/s42003-022-03099-0 -
Nature Communications Dec 2018The dynamic nature of the chromatin epigenetic landscape plays a key role in the establishment and maintenance of cell identity, yet the factors that affect the dynamics...
The dynamic nature of the chromatin epigenetic landscape plays a key role in the establishment and maintenance of cell identity, yet the factors that affect the dynamics of the epigenome are not fully known. Here we find that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 preferentially colocalize with epigenetic marks of active chromatin, and with cell-type specific enhancers. Loss of HMGNs enhances the rate of OSKM induced reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem cells (iPSCs), and the ASCL1 induced conversion of fibroblast into neurons. During transcription factor induced reprogramming to pluripotency, loss of HMGNs accelerates the erasure of the MEF-specific epigenetic landscape and the establishment of an iPSCs-specific chromatin landscape, without affecting the pluripotency potential and the differentiation potential of the reprogrammed cells. Thus, HMGN proteins modulate the plasticity of the chromatin epigenetic landscape thereby stabilizing, rather than determining cell identity.
Topics: Animals; Cell Differentiation; Cell Membrane; Cells, Cultured; Cellular Reprogramming; Chromatin; Embryo, Mammalian; Epigenesis, Genetic; Fibroblasts; HEK293 Cells; HMGN1 Protein; HMGN2 Protein; Humans; Induced Pluripotent Stem Cells; Male; Mice, Knockout; Mice, Nude; Protein Binding
PubMed: 30532006
DOI: 10.1038/s41467-018-07687-9 -
Molekuliarnaia Biologiia 2018HMGB proteins are involved in structural rearrangements caused by regulatory chromatin remodeling factors. Particular interest is attracted to a DNA chaperone mechanism,... (Review)
Review
HMGB proteins are involved in structural rearrangements caused by regulatory chromatin remodeling factors. Particular interest is attracted to a DNA chaperone mechanism, suggesting that the HMGB proteins introduce bends into the double helix, thus rendering DNA accessible to effector proteins and facilitating their activity. The review discusses the role that the HMBG proteins play in key intranuclear processes, including assembly of the preinitiation complex during transcription of ribosomal genes; transcription by RNA polymerases I, II, and III; recruitment of the SWI/SNF complex during transcription of nonribosomal genes; DNA repair; etc. The functions of the HMGB proteins are considered in detail with the examples of yeast HMO1 and NHP6. The two proteins possess unique features in adition to properties characteristic of the HMGB proteins. Thus, NHP6 stimulates a large-scale ATP-independent unwrapping of nucleosomal DNA by the FACT complex, while in its absence FACT stabilizes the nucleosome. HMO1 acts as an alternative linker histone. Both HMO1 and NHP6 are of applied interest primarly because they are homologs of human HMGB1, an important therapeutic target of anticancer and anti-inflammatory treatments.
Topics: Chromatin; DNA; HMGB Proteins; HMGN Proteins; High Mobility Group Proteins; Histones; Humans; Molecular Chaperones; Nucleosomes; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 30363049
DOI: 10.1134/S0026898418050099